Chapter 36, Ep 1 of 5: Tumor Screening and Reflex Testing

Episode one of the Hereditary GI Cancer Syndromes chapter builds the diagnostic framework the rest of the series depends on. The organizing idea: universal tumor testing catches the carriers that pedigree gatekeeping misses, because family history alone overlooks thirty to fifty percent of them. The four-protein immunohistochemistry pattern then decides the next move, with combined MLH1 and PMS2 loss running a sporadic-cancer rule-out before germline sequencing and everything else reflexing straight to the blood test. The through-line is that protein-loss pattern drives testing, and once a proband is confirmed, cascade testing of relatives becomes the highest-yield step.   Topics covered Why tumor testing replaces pedigree gatekeeping Universal four-protein MMR immunohistochemistry Universal endometrial IHC and the sentinel cancer The reflex pathway and IHC patterns MLH1 and PMS2 loss with the BRAF and methylation gate EPCAM and the MSH2 and MSH6 pattern Multi-gene panels and phenotype overlap Cascade testing and multidisciplinary referral   Key decisions Run universal four-protein mismatch-repair immunohistochemistry, MLH1, MSH2, MSH6, and PMS2, on every newly diagnosed colorectal and endometrial cancer, because pedigree-based screening misses thirty to fifty percent of carriers. On combined MLH1 and PMS2 loss, test the tumor for BRAF V600E first and then MLH1 promoter methylation; only when both are absent does the patient reflex to germline sequencing, because roughly seventy percent of that pattern is sporadic. Isolated loss of MSH2, MSH6, or PMS2 has no sporadic counterpart and reflexes directly to germline sequencing without the BRAF and methylation gate. On the combined MSH2 and MSH6 pattern, the germline test must include EPCAM, because three-prime EPCAM deletions silence the MSH2 promoter and mimic a primary MSH2 mutation. Choose the multi-gene panel by dominant clinical phenotype, and require pre-test counseling before drawing blood because positive, negative, and uncertain results all carry consequences. Once a pathogenic variant is confirmed in the proband, prioritize cascade testing of first-degree relatives, each of whom is fifty-fifty at risk and carries the same surveillance program.   For the full chapter with MCQs, tables, and primary-guideline references, visit www.boardpearls.com. Questions or feedback: [email protected]. (00:00) - The framework runs on tumor biology (00:57) - Universal four-protein immunohistochemistry (01:30) - Endometrial IHC and the sentinel cancer (02:04) - The reflex pathway by IHC pattern (02:19) - MLH1 and PMS2 loss, the sporadic gate (04:19) - EPCAM in the MSH2 differential (05:33) - Multi-gene panels and phenotype overlap (06:59) - Referral and keeping surveillance from lapsing